title: Angiogenic and vasoprotective effects of adrenomedullin on prevention of cognitive decline after chronic cerebral hypoperfusion in mice.
abstract: OBJECTIVE
  Although subcortical vascular dementia, the major subtype of vascular dementia, is caused by a disruption in white matter integrity after cerebrovascular insufficiency, no therapy has been discovered that will restore cerebral perfusion or functional cerebral vessels. Because adrenomedullin (AM) has been shown to be angiogenic and vasoprotective, the purpose of the study was to investigate whether AM may be used as a putative treatment for subcortical vascular dementia.
  
  
  METHODS
  A model of subcortical vascular dementia was reproduced in mice by placing microcoils bilaterally on the common carotid arteries. Using mice overexpressing circulating AM, we assessed the effect of AM on cerebral perfusion, cerebral angioarchitecture, oxidative stress, white matter change, cognitive function, and brain levels of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor.
  
  
  RESULTS
  After bilateral common carotid artery stenosis, mice overexpressing circulating AM showed significantly faster cerebral perfusion recovery due to substantial growth of the capillaries, the circle of Willis, and the leptomeningeal anastomoses and reduced oxidative damage in vascular endothelial cells compared with wild-type mice. Vascular changes were preceded by upregulation of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. White matter damage and working memory deficits induced by bilateral common carotid artery stenosis were subsequently restored in mice overexpressing circulating AM.
  
  
  CONCLUSIONS
  These data indicate that AM promotes arteriogenesis and angiogenesis, inhibits oxidative stress, preserves white matter integrity, and prevents cognitive decline after chronic cerebral hypoperfusion. Thus, AM may serve as a strategy to tackle subcortical vascular dementia.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Takakuni
authors.initials: T
authors.lastname: Maki
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
authors.forename: Youshi
authors.initials: Y
authors.lastname: Fujita
authors.forename: Takuo
authors.initials: T
authors.lastname: Nambu
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Miyashita
authors.forename: Mahito
authors.initials: M
authors.lastname: Yamada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Washida
authors.forename: Keiko
authors.initials: K
authors.lastname: Nishio
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.forename: Hideki
authors.initials: H
authors.lastname: Yokoi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tomimoto
mesh_terms: D053607:Adrenomedullin / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D020520:Brain Infarction / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D002536:Cerebral Arteries / Q000187:drug effects* / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D020925:Hypoxia-Ischemia, Brain / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology
chemical_list: D053607:Adrenomedullin